YAJEM-58031; No of Pages 6

American Journal of Emergency Medicine xxx (xxxx) xxx

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

Diagnostic accuracy of presepsin for sepsis by the new

Sepsis-3 definitions
Tomonori Yamamoto, MD, PhD a,⁎, Tetsuro Nishimura, MD, PhD a, Shinichiro Kaga, MD a,
Kenichiro Uchida, MD, PhD a, Yosuke Tachibana, MD a, Maiko Esaki, MD a, Wakaba Fukushima, MD b,c,
Kyoko Kondo, MD, PhD c, Yasumitsu Mizobata, MD, PhD a
a
Department of Traumatology and Critical Care Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
b
Department of Public Health, Osaka City University Graduate School of Medicine, Osaka, Japan
c
Research Support Platform, Osaka City University Graduate School of Medicine, Osaka, Japan

a r t i c l e i n f o

Article history:
Received 1 September 2018
Received in revised form 8 January 2019
Accepted 14 January 2019
Available online xxxx

© 2019 Elsevier Inc. All rights reserved.

Keywords:
Sepsis
Sepsis without shock
New definitions
Early diagnosis
1. Introduction
Presepsin
Early diagnosis of sepsis in the Emergency Department and intensive
care unit (ICU) is important when treating septic patients. Novel bio-
markers of sepsis have been developed and are being widely adopted
in clinical settings. Among them, procalcitonin (PCT) has been widely
used as biomarker in septic patients but has limited specificity. It in-
creases transiently in patients with non-septic conditions and systemic
inflammatory response syndromes (SIRS) (e.g., trauma, surgery, and
heatstroke) [1].
Cluster of differentiation 14 (CD14) is a free fragment of glycopro-
tein expressed on monocytes and macrophages. It serves as a receptor
of the lipopolysaccharide (LPS)-lipopolysaccharide binding protein
complexes. Its soluble form, soluble CD14 (sCD14), is produced from
cell secretion or when membrane-bound, CD14 (mCD14) detaches
from cells such as phagocytes. The N-terminal fragments of 13 kDa con-
sist of s CD14 subtype (sCD14-ST) called presepsin are related to medi-
ating the immune response to LPS [2]. Presepsin is currently under
investigation in clinical practice as a new biomarker of sepsis [3,4].
Four meta-analyses suggested that presepsin showed moderate diag-
⁎ Corresponding author at: Department of Traumatology and Critical Care Medicine,
Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka
545-8585, Japan.
E-mail address: m1162149@med.osaka-cu.ac.jp (T. Yamamoto).
nostic capacity for the detection of sepsis and may be a helpful and valu-
able biomarker in the early diagnosis of sepsis [5-8].
The Third International Consensus Definitions for Sepsis and Septic
Shock (Sepsis-3) recently presented new definitions for sepsis and sep-
tic shock [9]. The international consensus has defined sepsis as life-
threatening organ dysfunction caused by a dysregulated host response
to infection, but there has been little discussion about exactly how to de-
termine whether infection is suspected. There are no clear guidelines to
help the clinician identify the presence of early infection. Biomarkers for
early diagnosis of infection are expected because a long time is required
to evaluate clinical infection and obtain microbiological culture data in
clinical practice before a diagnosis of infection can be made. It might
be easy to diagnose septic shock in the early phase because these pa-
tients are truly critically ill and require catecholamine treatment. The
early diagnosis of sepsis in patients without shock or obvious infection
with systemic inflammation remains the most challenging problem.
Most of the recent studies have discussed biomarkers for sepsis includ-
ing shock, but no reports are currently available on diagnostic markers
of sepsis without shock under the new definitions. Thus, the aim of
this study was to investigate the diagnostic accuracy of presepsin com-
pared to other biomarkers of sepsis, especially sepsis without shock, by
the new Sepsis-3 definitions.

https://doi.org/10.1016/j.ajem.2019.01.025
0735-6757/© 2019 Elsevier Inc. All rights reserved.

Please cite this article as: T. Yamamoto, T. Nishimura, S. Kaga, et al., Diagnostic accuracy of presepsin for sepsis by the new Sepsis-3 definitions,
American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2019.01.025
2 T. Yamamoto et al. / American Journal of Emergency Medicine xxx (xxxx) xxx
2. Material and methods
2.1. Patient inclusion and exclusion criteria
This prospective study was performed in the ICU of a tertiary univer-
sity hospital. Inclusion criteria were patients fulfilling both SIRS criteria
and an acute change in total Sequential Organ Failure Assessment
(SOFA) score of 2 or more who were admitted to our ICU from February
2014 to August 2015. Exclusion criteria were age b18 years, post cardiac
arrest syndrome, and a SOFA score of b2.
We retrospectively divided the patients into three groups based on
the new definitions for sepsis: non-sepsis group, sepsis group, and sep-
tic shock group. Septic shock was defined as a change in SOFA score N2,
hypotension with vasopressors, and a lactate level N2 mmol/L. Blood
samples for biomarker measurements of presepsin, PCT, C-reactive pro-
tein (CRP), and white blood cells (WBC) were collected immediately
after clinical onset of disease resulting in an acute change in the total
SOFA score of 2 or more. A diagnosis of disseminated intravascular coag-
ulation (DIC) was made on the basis of the Japanese Association for
Acute Medicine DIC diagnostic criteria [10].
This study was approved by the institutional review boards of our
university and each participating institution. Written informed consent
was obtained from the patients or the patients' families at the clinical
onset of symptoms fulfilling the criteria for SIRS.
2.2. Diagnosis of infection
Evaluation of infection in our study was based on clinical course, im-
aging tests, and laboratory findings according to the criteria of the Inter-
national Sepsis Forum Consensus Conference on Definitions of Infection
[11]. The six most common infectious conditions were identified as
pneumonia, bloodstream infections, intravascular catheter-related sep-
sis, intra-abdominal infections, and urinary tract and skin, and soft-
tissue infections. After the end of hospital treatment, three study physi-
cians independently reviewed all clinical data of the study patients and
determined the presence of infection based on the above criteria. The
study physicians were blinded to the results of tested biomarker mea-
surements, such as presepsin, PCT, CRP, and WBC.
Fig. 1. Patient enrollment and classification. ICU, intensive care unit; SIRS, systemic inflammatory response syndromes; SOFA, Sequential Organ Failure Assessment.
Please cite this article as: T. Yamamoto, T. Nishimura, S. Kaga, et al., Diagnostic accuracy of presepsin for sepsis by the new Sepsis-3 definitions,
American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2019.01.025
2.3. Statistical analysis
To estimate the sample size, we assumed the incidence of sepsis in
the patients with high presepsin levels to be 70% and the incidence of
sepsis in the patients with low presepsin levels to be 30% based on the
results of the previous study [12]. Assuming 90% power with a 2-sided
α levels of 0.05, this study required a total of 72 patients to detect the
significance in 40% difference between the groups. Continuous variables
were given as median and interquartile range and were compared using
the Mann-Whitney U test. Between-group differences in categorical
variables were compared using Fisher's exact test or a χ2 test as appro-
priate. The Kruskal-Wallis test with Bonferroni correction for multi-
group comparisons was used to explore the results in each group
(non-sepsis, sepsis, and septic shock) at the first clinical onset of a
SOFA score of 2 or more. A receiver operating characteristic (ROC) anal-
ysis was performed for each of the biomarkers, and their diagnostic per-
formance for septic shock/sepsis without shock vs. non-sepsis or sepsis
without shock vs. non-sepsis were compared and the areas under the
ROC curves (AUCs) were determined. The optimal cutoff values for
each of the biomarkers in this study population were calculated for
each ROC curve through the Youden index (corresponding to the max-
imum of the sum “sensibility + specificity”). On the basis of cutoff
values, prognostic parameters (sensitivity, specificity, positive predic-
tive value (PPV), negative predictive value (NPV)) and accuracy were
also calculated.
For the multivariable analysis, odds ratios (OR) for septic shock/sep-
sis without shock compared to non-sepsis and sepsis without shock
compared to non-sepsis in relation to the levels of each diagnostic
marker and their 95% confidence intervals (CI) for the explanatory var-
iables were computed using a logistic regression model. Variables for p
b 0.20 in univariate analysis or those including age, CRP and WBC con-
sidered as medically significant or having potential associations with
sepsis from previous studies [9,13,14] were employed in the multivari-
able analysis. Finally, we performed a multivariable logistic regression
analysis adjusted for sex, age, SOFA score, presepsin, PCT, CRP, and
WBC to evaluate the relations between these biomarkers. We did not
use the APACHE II score as an adjustment variables because not all pa-
tients in this study were included within 24 h after admission. The cutoff
values for each of the biomarkers from previous studies [13,14] were
used in the multivariable analysis. We used the following cut-off values
for the diagnosis of sepsis: 600 pg/mL for presepsin, 0.96 ng/mL for PCT,
8.4 mg/dL for CRP from recent systemic and meta-analysis [13], and
 T. Yamamoto et al. / American Journal of Emergency Medicine xxx (xxxx) xxx 3

Table 1 between the non-sepsis そ group and the sepsis group in SOFA score
Patient characteristics. (p = 0.20).
Characteristic Non-sepsis Sepsis Septic The definitive diagnosis and infectious foci of patients included in
shock the study as obtained by analysis of the patients' digital medical records
n = 29 n = 29 n = 33 p are shown in Table 2. CRP and WBC values were not significantly differ-
value ent between each group, but the median concentrations of PCT and
Male, n (%) 15 (52) 19 (66) 24 (73) 0.13 presepsin were significantly higher in both the sepsis and septic shock
Age (years) 66 (43–74) 63 (40–79) 69 (58–77) 0.39 groups compared to the non-sepsis group (non-sepsis vs. sepsis vs. sep-
SOFA score 5 (4–7) 6 (4–9) 12 (9–14) b0.001 tic shock group: PCT, 0.6 vs. 1.4 vs. 11.0 ng/mL, p b 0.001; presepsin, 349
Shock, n (%) 4 (14) 0 (0) 33 (100) b0.001 vs. 817 vs. 1217 pg/mL, p b 0.001) (Fig. 2).
DIC, n (%) 3 (27) 14 (48) 22 (67) b0.001
Renal replacement therapy, n (%) 0 (0) 4 (14) 12 (36) 0.005
The area under the curve (AUC) values of presepsin to distinguish
In-hospital mortality, n (%) 1 (3) 3 (10) 13 (39) b0.001 sepsis including shock (septic shock/sepsis group) from non-sepsis
(non-sepsis group) were 0.88 (95% CI, 0.77–0.94) for presepsin, 0.81
Abbreviations: SOFA, sequential organ failure assessment; DIC, disseminated intravascular
coagulation. (95% CI, 0.71–0.88) for procalcitonin, 0.65 (95% CI, 0.53–0.75) for CRP,
Data are presented as median (25th to 75th percentile). and 0.57 (95% CI, 0.45–0.68) for WBC (Fig. 3a). In the other hand, the
area under the curve (AUC) values of presepsin to distinguish sepsis
without shock (sepsis group) from non-sepsis (non-sepsis group)
b4000 or N12,000/mm3 for WBC from the definition of SIRS [14]. The were 0.90 (95% CI, 0.76–0.96) for presepsin, 0.71 (95% CI, 0.57–0.83)
multivariable analysis using the optimal cutoff values for each of the for procalcitonin, 0.67 (95% CI, 0.52–0.79) for CRP, and 0.57 (95% CI,
biomarkers in this study population from ROC analysis was not 0.42–0.72) for WBC (Fig. 3b). According to these AUC values, the sensi-
employed because such models were not appropriately fitted due to tivity, specificity, PPV, NPV, and accuracy of presepsin to diagnose septic
strong correlation between presepisin and sepsis. The values for contin- shock/sepsis using a cutoff value of 508 pg/mL were 87%, 86%, 93%, 76%,
uous variables, age and SOFA score in the multivariable analysis were and 87%, respectively; those of PCT were 68%, 86%, 91%, 56%, and 74%
categorized according to each mean value. A two-sided p value b0.05 using a cutoff value of 1.5 ng/mL; and those of CRP were 40%, 90%,
was considered statistically significant. Statistical analyses were per- 89%, 41%, and 56% using a cut-off value of 17.6 mg/dL. In the other
formed using JMP Version 11.2 and SAS 9.3 (SAS Institute Inc., Cary, NC). hand, those of presepsin to diagnose sepsis without shock using a cutoff
value of 557 pg/mL were 93%, 86%, 87%, 93%, and 90%, respectively;
those of PCT were 69%, 66%, 67%, 68%, and 67% using a cutoff value of
3. Results 0.79 ng/mL; and those of CRP were 66%, 62%, 63%, 64%, and 64% using
a cutoff value of 11.9 mg/dL.
Of 1014 patients admitted to the ICU during the 18-month study pe- A multivariable logistic regression analysis adjusted for sex, age,
riod, 109 consecutive patients fulfilled the SIRS criteria. After excluding SOFA score, presepsin, PCT, CRP, and WBC revealed that the OR of a
18 patients who did not meet the inclusion criteria, we enrolled 91 pa- high presepsin level (≥600 pg/mL) for sepsis including shock signifi-
tients with an acute change in total SOFA score of 2 or more. We divided cantly increased compared to that of a low presepsin level
these patients into three groups based on the new definitions for sepsis: (b600 pg/mL) (OR, 22.24; 95% CI, 5.59–121.88; p b 0.001) and the OR
non-sepsis group (n = 29), sepsis group (n = 29), and septic shock of a high PCT level (≥0.96 pg/mL) increased compared to that of a low
group (n = 33) (Fig. 1). Nine patients in the non-sepsis group and 11 PCT level (b0.96 pg/mL) (OR, 8.33; 95% CI, 2.27–36.69; p = 0.001).
patients in the sepsis group were included during their ICU stay (me- CRP, and WBC levels were not significantly associated with a diagnosis
dian: 8 [8-13] days, median: 8 [8-10] days, respectively). All other pa- of sepsis including shock (Table 3). The multivariable analysis also re-
tients were included at admission to the ICU. vealed that the OR of a high presepsin level for sepsis without shock sig-
Patient characteristics are presented in Table 1. The SOFA score at nificantly increased compared to that of a low presepsin level (OR,
the first clinical onset of an acute change in the total score of 2 or 24.30; 95% CI, 5.21–176.24; p b 0.001) and the OR of a high PCT level in-
more and the percentages of patients with shock, disseminated intra- creased compared to that of a low PCT level (OR, 4.97; 95% CI,
vascular coagulation, renal replacement therapy, and in-hospital mor- 1.11–26.27; p = 0.04). CRP, and WBC levels were not significantly asso-
tality were higher in the septic shock group than in the non-sepsis ciated with a diagnosis of sepsis without shock (Table 4).
group or sepsis group. However, there was no significant difference

Table 2
Definitive diagnosis and infectious sites of the patients.

Non-sepsis Sepsis Septic shock

n = 29 n = 29 n = 33

Definitive diagnosis, n (%) Primary site of infection, n (%)

Major trauma 12 (41.4) Pulmonary 11 (38.0) 12 (36.4)
GI bleeding 3 (10.4) Urinary tract 4 (13.8) 8 (24.2)
Stroke 3 (10.4) Intra-abdominal 6 (20.7) 3 (9.1)
Severe acute pancreatitis 2 (6.9) Skin and soft tissue 4 (13.8) 6 (18.2)
Burns 2 (6.9) Catheter related 2 (6.9) 0 (0)
Pulmonary embolism 1 (3.4) Bloodstream 1 (3.4) 1 (3.0)
Acute coronary syndrome 1 (3.4) No clear source 1 (3.4) 3 (9.1)
COPD 1 (3.4) Causative organisms, n (%)
Others 4 (13.8) Infecting organism identified 18 (62.1) 29 (87.9)
Blood culture positive 10 (34.5) 19 (58)
Gram-positive bacteria 14 (48.3) 14 (42.4)
Gram-negative bacteria 6 (20.7) 12 (36.4)
Others (fungi, etc.) 1 (3.4) 2 (6.1)

Abbreviations: COPD, chronic obstructive lung disease; GI, gastrointestinal.

Data are presented as number (%).

Please cite this article as: T. Yamamoto, T. Nishimura, S. Kaga, et al., Diagnostic accuracy of presepsin for sepsis by the new Sepsis-3 definitions,
American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2019.01.025
4 T. Yamamoto et al. / American Journal of Emergency Medicine xxx (xxxx) xxx

Fig. 2. Median values of diagnostic markers of sepsis in each group. White columns represent data for the non-sepsis group, light gray columns for the sepsis group, and dark gray columns
for the septic shock group. Lines denote median values, boxes represent 25th to 75th percentiles, and whiskers indicate the range. CRP, C-reactive protein; PCT, procalcitonin; WBC, white
blood cells.

4. Discussion A recent systematic review and meta-analysis reported that PCT,

This study investigated the diagnostic value of presepsin compared
to other biomarkers (PCT, CRP, and WBC) of sepsis, especially sepsis
without shock, considering the new Sepsis-3 definitions. Although no
significant difference was observed in SOFA scores in the non-sepsis
group and the sepsis group, the results showed that the AUC to distin-
guish septic shock/sepsis or non-sepsis and sepsis without shock or
non-sepsis were the highest for presepsin. The logistic regression anal-
ysis using another cutoff values from previous reports also revealed that
a high presepsin level was significantly associated with a diagnosis of
sepsis including shock or sepsis without shock.
CRP, and presepsin presented a moderate degree of diagnostic value
with AUCs of 0.85, 0.77, and 0.88, respectively [13]. However, new def-
initions for sepsis and septic shock were published under Sepsis-3 in
2016, but since then, only a few reports have been published on diag-
nostic markers of sepsis under the new definitions. All previous studies
classified patients as having SIRS, severe sepsis, and septic shock, or as
having SIRS and sepsis including severe sepsis/septic shock. Only a
few studies evaluated the diagnostic value of biomarkers including
presepsin by comparing patients with SIRS with sepsis versus patients
without severe sepsis/septic shock [12,15]. In addition, all previous
studies used univariate analysis to evaluate diagnostic markers of sepsis,

Fig. 3. Receiver operating characteristic curve for diagnostic markers of sepsis. The area under the curve for septic shock/sepsis without shock was 0.88 for presepsin, 0.81 for procalcitonin,
0.65 for CRP, and 0.57 for WBC (a). The area under the curve for sepsis without shock was 0.90 for presepsin, 0.71 for procalcitonin, 0.67 for CRP, and 0.57 for WBC (b). CRP, C-reactive
protein; WBC, white blood cells.

Please cite this article as: T. Yamamoto, T. Nishimura, S. Kaga, et al., Diagnostic accuracy of presepsin for sepsis by the new Sepsis-3 definitions,
American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2019.01.025
 T. Yamamoto et al. / American Journal of Emergency Medicine xxx (xxxx) xxx 5

Table 3 5. Conclusions
Odds ratios of each diagnostic marker level for sepsis including shock (septic shock and
sepsis group) compared to non-sepsis (non-sepsis group).
Presepsin appears to be useful in aiding in the diagnosis of sepsis in-
Univariable Multivariable cluding shock or especially sepsis without shock versus non-sepsis in
OR (95% CI) p value OR (95% CI) p value patients with a change in SOFA score of 2 or more. Additional prospec-
tive research may be needed to evaluate the diagnostic accuracy of
Sex
Male 2.42 (0.98–6.09) 0.006 4.56 (1.15–22.05) 0.03 presepsin for sepsis considering the new Sepsis-3 definitions.
Age (years)
≥65 1.20 (0.49–2.93) 0.69 0.85 (0.22–3.17) 0.81 List of abbreviations
SOFA score
≥5 6.30 (2.28–18.6) b0.001 1.90 (0.47–7.56) 0.36
Presepsin (pg/mL)
APACHE Acute Physiology and Chronic Health Evaluation
≥600 19.58 (6.42–74.98) b0.001 22.24 (5.59–121.88) b0.001 AUC area under the curve
PCT (ng/mL) CI confidence interval
≥0.96 7.62 (2.93–21.34) b0.001 8.33 (2.27–36.69) 0.001 CRP C-reactive protein
CRP (mg/dL)
ICU intensive care unit
≥8.4 1.60 (0.63–4.00) 0.32 0.59 (0.14–2.23) 0.44
WBC (/mm3) OR odds ratio
b4000, N12,000 0.89 (0.35–2.22) 0.81 0.79 (0.19–3.08) 0.73 ROC receiver operating characteristic
Abbreviations: SOFA, sequential organ failure assessment; CI, confidence interval; CRP, C-
PCT procalcitonin
reactive protein; PCT, procalcitonin; OR, odds ratio; WBC, white blood cells. Sepsis-3 Third International Consensus Definitions for Sepsis and Sep-
tic Shock
SIRS systemic inflammatory response syndromes
and no study has used multivariable analysis to evaluate the relations SOFA Sequential Organ Failure Assessment
between these biomarkers. WBC white blood cells
The OR of presepsin for sepsis including shock or sepsis without
shock compared to non-sepsis was significantly high among the bio- Ethics approval and consent to participate
markers for sepsis. In addition, this study revealed the higher OR of
presepsin for sepsis without shock than that of PCT. A few previous The study was carried out according to the principles of the declara-
studies have suggested that the presepsin concentration was signifi- tion of Helsinki and was approved by the Ethics Committee of Osaka
cantly higher in patients with sepsis in comparison to non-septic SIRS City University Hospital. Written informed consent was obtained from
patients [12,15], but these were reports of retrospective observational all participating patients or their families.
studies and the evaluation of biomarkers including presepsin was con-
ducted by univariate analysis. There was also some possibility of bias Consent for publication
in relation to each of the biomarkers at the time of diagnosis of sepsis.
Several limitations of this study should be acknowledged. First, we Not applicable.
used SIRS as the diagnosis for the first screening, so it is possible that pa-
tients who did not meet the SIRS criterion of a change in SOFA score of 2 Availability of data and material
or more were excluded from this study. The need for two or more SIRS
criteria to define severe sepsis excluded one of eight otherwise similar The data that support the findings of this study are available from
patients with infection and organ failure [16]. Second, this study ana- the corresponding author on request.
lyzed a limited number of patients from a single center. Third, this
study focused on the diagnostic value of biomarkers for sepsis, but we Competing interests
could not evaluate relations between the biomarkers and prognosis. Fu-
ture multicenter studies are needed to further evaluate diagnostic The authors declare that they have no competing interests.
markers including presepsin for sepsis under the new Sepsis-3
definitions. Funding

The study was funded through Department of Traumatology and

Table 4 Critical Care Medicine, Osaka City University Graduate School of
Odds ratios of each diagnostic marker level for sepsis without shock (sepsis group) com-
Medicine.
pared to non-sepsis (non-sepsis group).

Univariable Multivariable Authors' contributions

OR (95% CI) p value OR (95% CI) p value

Sex TY, HY, TN and YM conceived of the study. TY, NS, SK, KU and ME col-
Male 2.04 (0.72–6.00) 0.18 2.11 (0.45–11.17) 0.35 lected the data. TY, WF and KK performed the statistical analyses. TY
Age (years) drafted the manuscript. All authors contributed to the interpretation
≥65 0.76 (0.27–2.13) 0.6 0.37 (0.06–1.81) 0.23 of the data, revised the manuscript, and read and approved the final
SOFA score
manuscript.
≥5 2.45 (0.84–7.57) 0.1 0.94 (0.20–4.06) 0.94
Presepsin (pg/mL)
≥600 16.41 (4.71–70.56) b0.001 24.30 (5.21–176.24) b0.001 Acknowledgments
PCT (ng/mL)
≥0.96 3.64 (1.26–11.21) 0.017 4.97 (1.11–26.27) 0.04
Not applicable.
CRP (mg/dL)
≥8.4 1.85 (0.62–5.73) 0.27 1.00 (0.20–4.99) 0.99
WBC (/mm3)
b4000, N12,000 0.56 (0.19–1.61) 0.28 0.45 (0.08–2.04) 0.30

Abbreviations: SOFA, sequential organ failure assessment; CI, confidence interval; CRP, C-
reactive protein; PCT, procalcitonin; OR, odds ratio; WBC, white blood cells.

Please cite this article as: T. Yamamoto, T. Nishimura, S. Kaga, et al., Diagnostic accuracy of presepsin for sepsis by the new Sepsis-3 definitions,
American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2019.01.025
6 T. Yamamoto et al. / American Journal of Emergency Medicine xxx (xxxx) xxx
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